In the model for the development of pancreatic cancer, the pancreatic ducts undergo a progressive series of architectural, cytologic, and genetic changes that are defined by degrees of pancreatic intraepithelial neoplasia (PanIN). The evaluation of PanIN has been challenging due to limited in vitro and in vivo models. The recent development of a mouse PanIN model through targeted endogenous expression of a K-ras mutant allele, the earliest recognized human genetic aberrancy, recapitulates human PanIN and provides a necessary tool to study its mechanisms. Recently, our laboratory was the first to identify a potential role for chemokine receptor CXCR4 in the growth and proliferation of PanIN. Using mouse and human PanIN tissues, we observed absence of CXCR4 expression in histologically normal pancreatic ducts, but increased CXCR4 expression in PanIN lesions. We also noted that activation of the CXCR4 receptor, by its specific ligand CXCL12, resulted in enhanced PanIN cell proliferation (Gut, 2008). Dysregulated K-Ras signaling transforms pancreatic ducts into PanIN lesions, but it also appears that these K-Ras dependent changes may be further driven by activated CXCR4. The establishment and use of a mouse PanIN model is a necessary and uniquely available preclinical tool for the investigation of human PanIN. It will allow us to explore and modify CXCR4 signaling pathways and its mediators. We hypothesize that CXCR4 signaling is requisite for PanIN proliferation and progression. Since discrete CXCR4 signaling leading to enhanced PanIN and pancreatic cancer proliferation has not been defined, our objectives are to define CXCR4 signal transduction in this regard and to assess in vivo therapeutic targeting of specific CXCR4 signaling mediators to prevent the initial development of PanIN or prevent its progression to invasive and metastatic pancreatic cancer. We propose the following Aims: 1) Aim I: Characterize CXCR4 signaling associated with enhanced proliferation and identify optimal targets to antagonize CXCR4-enhanced proliferation. 2) Aim II: Determine whether downstream CXCR4 signaling is regulated by K-Ras. 3) Aim III: Determine whether therapeutic targeting of CXCR4 prevents or abrogates progression of PanIN into pancreatic cancer in an in vivo murine PanIN model. PUBLIC HEALTH RELEVANCE: Pancreatic cancer is a major cause of cancer-related deaths. Poor survival results from frequent recurrence after curative surgery and resistance to chemoradiation therapies. A better understanding of the pathogenesis of pancreatic cancer is clearly needed to improve clinical outcomes. The results of our proposed research studies can be applied to the prevention and/or treatment of human pancreatic disease.